OBJECTIVE: Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement.
METHODS: We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022.
RESULTS: Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%).
RESULTS: After a median 40 months\' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy.
CONCLUSIONS: In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

UNASSIGNED: Little is known about how the brains of autistic children process language during real-world \"social contexts,\" despite the fact that challenges with language, communication, and social interaction are core features of Autism Spectrum Disorder (ASD).
UNASSIGNED: We investigated the neural bases of language processing during social and non-social contexts in a sample of N=20 autistic and N=20 neurotypical (NT) preschool-aged children, 3 to 6 years old. Functional near-infrared spectroscopy (fNIRS) was used to measure children\'s brain response to \"live language\" spoken by a live experimenter during an in-person social context (i.e., book reading), and \"recorded language\" played via an audio recording during a non-social context (i.e., screen time). We examined within-group and between-group differences in the strength and localization of brain response to live language and recorded language, as well as correlations between children\'s brain response and language skills measured by the Preschool Language Scales.
UNASSIGNED: In the NT group, brain response to live language was greater than brain response to recorded language in the right temporal parietal junction (TPJ). In the ASD group, the strength of brain response did not differ between conditions. The ASD group showed greater brain response to recorded language than the NT group in the right inferior and middle frontal gyrus (IMFG). Across groups, children\'s language skills were negatively associated with brain response to recorded language in the right IMFG, suggesting that processing recorded language required more cognitive effort for children with lower language skills. Children\'s language skills were also positively associated with the difference in brain response between conditions in the right TPJ, demonstrating that children who showed a greater difference in brain response to live language versus recorded language had higher language skills.
UNASSIGNED: Findings should be considered preliminary until they are replicated in a larger sample.
UNASSIGNED: Findings suggest that the brains of NT children, but not autistic children, process language differently during social and non-social contexts. Individual differences in how the brain processes language during social and non-social contexts may help to explain why language skills are so variable across children with and without autism.

Arbuscular mycorrhizal (AM) symbiosis, the nutritional partnership between AM fungi and most plant species, is globally ubiquitous and of great ecological and agricultural importance. Studying the processes of AM symbiosis is confounded by its highly spatiotemporally dynamic nature. While microscopy methods exist to probe the spatial side of this plant-fungal interaction, the temporal side remains more challenging, as reliable deep-tissue time-lapse imaging requires both symbiotic partners to remain undisturbed over prolonged time periods. Here, we introduce the AMSlide: a noninvasive, high-resolution, live-imaging system optimised for AM symbiosis research. We demonstrate the AMSlide\'s applications in confocal microscopy of mycorrhizal roots, from whole colonisation zones to subcellular structures, over timeframes from minutes to weeks. The AMSlide\'s versatility for different microscope set-ups, imaging techniques, and plant and fungal species is also outlined. It is hoped that the AMSlide will be applied in future research to fill in the temporal blanks in our understanding of AM symbiosis, as well as broader root and rhizosphere processes.

The poultry industry is the largest source of meat and eggs for the growing human population worldwide. Key concerns in poultry farming are nutrition, management, flock health, and biosecurity measures. As part of the flock health, use of live viral vaccines plays a vital role in the prevention of economically important and common viral diseases. This includes diseases and production losses caused by Newcastle disease virus, infectious bronchitis virus, infectious laryngotracheitis virus, infectious bursal disease virus, Marek\'s disease virus, chicken infectious anemia virus, avian encephalomyelitis virus, fowlpox virus, and avian metapneumovirus. These viruses cause direct and indirect harms, such as financial losses worth millions of dollars, loss of protein sources, and threats to animal welfare. Flock losses vary by type of poultry, age of affected animals, co-infections, immune status, and environmental factors. Losses in broiler birds can consist of high mortality, poor body weight gain, high feed conversion ratio, and increased carcass condemnation. In commercial layers and breeder flocks, losses include higher than normal mortality rate, poor flock uniformity, drops in egg production and quality, poor hatchability, and poor day-old-chick quality. Despite the emergence of technology-based vaccines, such as inactivated, subunit, vector-based, DNA or RNA, and others, the attenuated live vaccines remain as important as before. Live vaccines are preferred in the global veterinary vaccine market, accounting for 24.3% of the global market share in 2022. The remaining 75% includes inactivated, DNA, subunit, conjugate, recombinant, and toxoid vaccines. The main reason for this is that live vaccines can induce innate, mucosal, cellular, and humoral immunities by single or multiple applications. Some live vaccine combinations provide higher and broader protection against several diseases or strains of viruses. This review aimed to explore insights on the pros and cons of attenuated live vaccines commonly used against major viral infections of the global chicken industry, and the future road map for improvement.
Estudio recapitulativo- Pros y contras del uso de vacunas virales vivas en parvadas de pollos comerciales. La industria avícola es la mayor fuente de carne y huevos para la creciente población humana en todo el mundo. Las principales preocupaciones en la avicultura son la nutrición, el manejo, la salud de las parvadas y las medidas de bioseguridad. Como parte de la salud de las parvadas avícolas, el uso de vacunas virales vivas juega un papel vital en la prevención de enfermedades virales comunes y de importancia económica. Esto incluye enfermedades y pérdidas en la producción causadas por el virus de la enfermedad de Newcastle, el virus de la bronquitis infecciosa, el virus de la laringotraqueítis infecciosa, el virus de la enfermedad infecciosa de la bolsa, el virus de la enfermedad de Marek, el virus de la anemia infecciosa del pollo, el virus de la encefalomielitis aviar, el virus de la viruela aviar y el metapneumovirus aviar. Estos virus causan daños directos e indirectos, como pérdidas financieras valoradas en millones de dólares, pérdida de fuentes de proteínas y amenazas al bienestar animal. Las pérdidas en las parvadas avícolas varían según el tipo de aves, la edad de los animales afectados, las coinfecciones, el estado inmunológico y los factores ambientales. Las pérdidas en aves de engorde pueden consistir en una alta mortalidad, un pobre aumento de peso corporal, un alto índice de conversión alimenticia y un mayor decomiso de las canales. En las gallinas de postura comerciales y en las parvadas de reproductoras, las pérdidas incluyen una tasa de mortalidad superior a la normal, una escasa uniformidad de la parvada, caídas en la producción y calidad de los huevos, una pobre incubabilidad y una mala calidad de los pollitos de un día. A pesar de la aparición de vacunas de base tecnológica, como las inactivadas, subunitarias, vectoriales, de ADN o ARN, entre otras, las vacunas vivas atenuadas siguen siendo tan importantes como antes. Las vacunas vivas son las preferidas en el mercado mundial de vacunas para uso veterinario y representaron el 24.3% de la cuota de mercado mundial en el año 2022. El 75% restante incluye vacunas inactivadas, de ADN, de subunidades, conjugadas, recombinantes y toxoides. La razón principal de esto es que las vacunas vivas pueden inducir inmunidad innata, de mucosas, celular y humoral mediante aplicaciones únicas o múltiples. Algunas combinaciones de vacunas vivas brindan una protección mayor y más amplia contra varias enfermedades o cepas de virus. Esta revisión tuvo como objetivo explorar ideas sobre los pros y los contras de las vacunas vivas atenuadas comúnmente utilizadas contra las principales infecciones virales de la industria avícola mundial, y las rutas futuras para mejorar.

Under the background of food security, using non-grain feed instead of corn-soybean-based feed is an effective measure to alleviate the food-feed competition. While, non-grain feeds are often rich in fiber, which cannot be digested by non-ruminants. Producing heterologous enzymes in non-ruminants to improve cellulose utilization rate is a new research strategy by transgenic technology. In this study, porcine transthyretin (TTR) promoter, signal peptide-coding sequence (CDS), Saccharomycopsis fibuligera β-glucosidase gene (BGL1)-CDS, 6×His sequences fragments were fused into pGL3-control vector to generate transgenic vector. Then, transgenic mice were generated by pronuclear microinjection of the linearized expression vectors. Transgenic mice and their offspring were examined by PCR-based genotyping and copy number variation. Results showed that BGL1 was successfully integrated into the mouse genome and transmitted stably. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and β-glucosidase activity assay demonstrated that BGL1 was specifically expressed in the liver, and β-glucosidase activity significantly increased. In addition, liver weight index, cellular morphology, and collagen fiber content of the liver showed that exogenous gene insertion did not cause any lesions to live. Taken together, our findings suggest that β-glucosidase driven by TTR promoter was specifically expressed in the liver of transgenic mice.

Current SARS-CoV-2 vaccines provide protection for COVID-19-associated hospitalization and death, but remain inefficient at inhibiting initial infection and transmission. Despite updated booster formulations, breakthrough infections and reinfections from emerging SARS-CoV-2 variants are common. Intranasal vaccination to elicit mucosal immunity at the site of infection can improve the performance of respiratory virus vaccines. We developed SARS-CoV-2 M2SR, a dual SARS-CoV-2 and influenza vaccine candidate, employing our live intranasal M2-deficient single replication (M2SR) influenza vector expressing the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein of the prototype strain, first reported in January 2020. The intranasal vaccination of mice with this dual vaccine elicits both high serum IgG and mucosal IgA titers to RBD. Sera from inoculated mice show that vaccinated mice develop neutralizing SARS-CoV-2 antibody titers against the prototype and Delta virus strains, which are considered to be sufficient to protect against viral infection. Moreover, SARS-CoV-2 M2SR elicited cross-reactive serum and mucosal antibodies to the Omicron BA.4/BA.5 variant. The SARS-CoV-2 M2SR vaccine also maintained strong immune responses to influenza A with high titers of anti H3 serum IgG and hemagglutination inhibition (HAI) antibody titers corresponding to those seen from the control M2SR vector alone. With a proven safety record and robust immunological profile in humans that includes mucosal immunity, the M2SR influenza viral vector expressing key SARS-CoV-2 antigens could provide more efficient protection against influenza and SARS-CoV-2 variants.

The study aims to identify the mechanisms underlying the findings that will to exist, live, survive and fight (WTELS-F) optimizes executive functions. Defining executive functions (EF) as having cold (working memory, inhibition, and cognitive flexibility) and hot (e.g., motivation) components, we hypothesized that WTELS-F affects executive functions positively via two pathways. The first pathway is through the hot executive function (motivation), and the second is via survival or existential processing. In a longitudinal study of 228 adult participants two times with ten weeks in between, we used measures for WTELS-F, working memory, inhibition, shift/cognitive flexibility, and self-motivation. We tested the structural validity of the four factors\' executive function by exploratory factor analysis in time 1 data and confirmatory factor analysis in time 2 data. We conducted structural equation modeling WTELS-F change as a latent variable predicted by the change in its three components between times 1 and 2., affecting changes in self-motivation (the hot EF), and changes in the latent variable of cold EF as predicted by changes in working memory, inhibition, and shift. Results indicated that the model of EF fit the data well without modification. WTELS-F significantly affected self-motivation (the hot EF) and the cold EF longitudinally. It had further mediated effects on cold EF via its impact on self-motivation. The results provided evidence for the two pathways hypothesis of the effects of WTELS-F on EF. The conceptual and clinical implications of these findings were discussed.

We previously demonstrated that an intranasal dose of 108 50% tissue culture infectious dose (TCID50) M2-deficient single replication (M2SR) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection.
Serosusceptible subjects aged 18-49 years were randomized to receive 2 doses (108-109 TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines.
The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%-56.7%) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI, 61.4%-92.3%) after 109 dose (P < .001). A single 109 TCID50 dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%-85.8%) of recipients. Mucosal and cellular immune responses were also induced.
These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza.
NCT03999554.
In recent years, influenza A H3N2 viruses have evolved into multiple cocirculating clades, resulting in low vaccine efficacy and highlighting the need for more effective influenza vaccines. In a previous challenge study, a single intranasal dose of the investigational vaccine M2SR demonstrated protection against a highly drifted H3N2 influenza challenge virus in a subset of vaccine recipients with a signature immune response. Increasing the dose of the M2SR vaccine in this phase1b study demonstrated a statistically significant increase in the proportion of subjects with the signature immune responses seen previously. The vaccine-induced antibodies were cross-reactive with a panel of drifted H3N2 viruses from 2007 to 2019. Additionally, M2SR generated a rise in serum hemagglutination inhibition antibody titer in 71% of subjects. In contrast, the H3N2 seroresponse rate for the licensed intranasal vaccine FluMist is 10% in seronegative adults. Moreover, M2SR elicited mucosal and cell-mediated immune responses. This study demonstrates that the intranasal M2SR generates a multifaceted immune response and has the potential to provide better efficacy against vaccine-matched strains and influenza drift variants reducing the need to update the vaccine on an annual basis. This is a noteworthy step in the development of a broadly protective influenza vaccine.

Science is justly admired as a cumulative process (\"standing on the shoulders of giants\"), yet scientific knowledge is typically built on a patchwork of research contributions without much coordination. This lack of efficiency has specifically been addressed in clinical research by recommendations for living systematic reviews and against research waste. We propose to further those recommendations with ALL-IN meta-analysis: Anytime Live and Leading INterim meta-analysis. ALL-IN provides statistical methodology for a meta-analysis that can be updated at any time-reanalyzing after each new observation while retaining type-I error guarantees, live-no need to prespecify the looks, and leading-in the decisions on whether individual studies should be initiated, stopped or expanded, the meta-analysis can be the leading source of information. We illustrate the method for time-to-event data, showing how synthesizing data at interim stages of studies can increase efficiency when studies are slow in themselves to provide the necessary number of events for completion. The meta-analysis can be performed on interim data, but does not have to. The analysis design requires no information about the number of patients in trials or the number of trials eventually included. So it can breathe life into living systematic reviews, through better and simpler statistics, efficiency, collaboration and communication.

BPZE1 is a live, attenuated pertussis vaccine derived from B. pertussis strain Tohama I modified by genetic removal or inactivation of 3 B. pertussis toxins: pertussis toxin, dermonecrotic toxin, and tracheal cytotoxin. This Phase 2a study evaluated the safety and immunogenicity of liquid or lyophilized BPZE1 vaccine administered intranasally by needleless tuberculin syringe or mucosal atomization device (VaxINatorTM) at two dose levels.
Fifty healthy male and non-pregnant female participants 18-49 years of age were enrolled. Participants were randomized 3:3:3:1 to a single lyophilized dose of 107 colony forming units (CFU) BPZE1, 109 CFU BPZE1, placebo via VaxINator device, or a single liquid dose of 109 CFU BPZE1 via tuberculin syringe. Reactogenicity was assessed for 14 days. Blood was obtained pre-vaccination; on Day 8 (safety); and on Days 15, 29, and 181 (immunogenicity). Nasal wick and swab samples were obtained at baseline and on Days 29 and 181 for assessment of mucosal antibody responses and clearance of BPZE1.
Across all groups, 35/50 (70 %) experienced at least one local adverse event (AE) and 31/50 (62 %) experienced at least one systemic AE, with similar AE frequencies observed between the highest 109 CFU BPZE1 and placebo groups. There were no severe or serious AEs during the study. At Day 29, seroconversion (≥2-fold rise from baseline in serum IgG or IgA) to at least 2 pertussis antigens was observed in 73 % in the 109 CFU BPZE1 VaxINator group, 60 % in the 109 CFU BPZE1 group delivered via tuberculin syringe, 27 % of participants in the 107 CFU BPZE1 VaxINator group, and 20 % in the placebo VaxINator group. No participants were colonized with BPZE1 at Day 29 post vaccination.
Lyophilized BPZE1 vaccine was well tolerated and immunogenic at the highest dose (109 CFU) delivered intranasally by VaxINator device and was not associated with any SAEs or prolonged shedding of BPZE1. Further evaluation of BPZE1 is warranted.